OA16582A - Process for the preparation of anagrelide and analogues thereof. - Google Patents
Process for the preparation of anagrelide and analogues thereof. Download PDFInfo
- Publication number
- OA16582A OA16582A OA1201300158 OA16582A OA 16582 A OA16582 A OA 16582A OA 1201300158 OA1201300158 OA 1201300158 OA 16582 A OA16582 A OA 16582A
- Authority
- OA
- OAPI
- Prior art keywords
- formula
- compound
- hydrogen
- process according
- mixture
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 77
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N Anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 title abstract description 29
- 229960001694 anagrelide Drugs 0.000 title abstract description 27
- 150000001875 compounds Chemical class 0.000 claims description 109
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 150000002466 imines Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 229910052720 vanadium Inorganic materials 0.000 claims description 11
- 239000004471 Glycine Substances 0.000 claims description 10
- 238000007792 addition Methods 0.000 claims description 10
- ATDGTVJJHBUTRL-UHFFFAOYSA-N Cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 239000003638 reducing agent Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000000802 nitrating Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 230000000903 blocking Effects 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 230000002503 metabolic Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000002194 synthesizing Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 64
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 238000010992 reflux Methods 0.000 description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- -1 2,3-dichloro-6-nitrobenzyl halide Chemical class 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 description 12
- WIYQPLPGNFOLGH-UHFFFAOYSA-N 2,3-dichloro-6-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(Cl)=C1C=O WIYQPLPGNFOLGH-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 10
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 239000001187 sodium carbonate Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical group [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000001117 sulphuric acid Substances 0.000 description 8
- 235000011149 sulphuric acid Nutrition 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 238000005755 formation reaction Methods 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 230000001965 increased Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 5
- ZIPMYVOSCREWFV-UHFFFAOYSA-N 2-[(6-amino-2,3-dichlorophenyl)methyl-ethylamino]acetic acid Chemical compound OC(=O)CN(CC)CC1=C(N)C=CC(Cl)=C1Cl ZIPMYVOSCREWFV-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 241000894007 species Species 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000006396 nitration reaction Methods 0.000 description 4
- 230000000171 quenching Effects 0.000 description 4
- PBVMRNDKKQMKFM-UHFFFAOYSA-N 2-[tert-butyl-[(2,3-dichloro-6-nitrophenyl)methyl]amino]acetic acid Chemical compound OC(=O)CN(C(C)(C)C)CC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O PBVMRNDKKQMKFM-UHFFFAOYSA-N 0.000 description 3
- QFHPUEPQOHXZSF-UHFFFAOYSA-N 2-amino-2-methylpropanoic acid;hydrochloride Chemical compound Cl.CC(C)(N)C(O)=O QFHPUEPQOHXZSF-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 208000002047 Essential Thrombocythemia Diseases 0.000 description 3
- 206010028576 Myeloproliferative disease Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- YREPHXXOTHNLEV-UHFFFAOYSA-N ethyl 2-amino-2-methylpropanoate;hydrochloride Chemical compound Cl.CCOC(=O)C(C)(C)N YREPHXXOTHNLEV-UHFFFAOYSA-N 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 230000001131 transforming Effects 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- FUOOLUPWFVMBKG-UHFFFAOYSA-N α-aminoisobutanoic acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 210000001772 Blood Platelets Anatomy 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N Methyl isopropyl ketone Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N Methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N Tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atoms Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000003951 lactams Chemical group 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000004301 light adaptation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XYKIUTSFQGXHOW-UHFFFAOYSA-N propan-2-one;toluene Chemical compound CC(C)=O.CC1=CC=CC=C1 XYKIUTSFQGXHOW-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 229940013123 stannous chloride Drugs 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- NVQPKDBOSKBIEX-UHFFFAOYSA-N (2,3-dichloro-6-nitrophenyl)methanamine Chemical compound NCC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O NVQPKDBOSKBIEX-UHFFFAOYSA-N 0.000 description 1
- OCSXCROLWYVFAO-UHFFFAOYSA-N (2,3-dichloro-6-nitrophenyl)methanol Chemical compound OCC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O OCSXCROLWYVFAO-UHFFFAOYSA-N 0.000 description 1
- MBNMGGKBGCIEGF-UHFFFAOYSA-N 1,1-diethoxypropane Chemical compound CCOC(CC)OCC MBNMGGKBGCIEGF-UHFFFAOYSA-N 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-Dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 1
- ZIZYIDMRRKTXEE-UHFFFAOYSA-N 1,2-dichloro-3-methyl-4-nitrobenzene Chemical compound CC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O ZIZYIDMRRKTXEE-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CAFAOQIVXSSFSY-UHFFFAOYSA-N 1-ethoxyethanol Chemical compound CCOC(C)O CAFAOQIVXSSFSY-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-Dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- UVQPJOHHDFHYEE-UHFFFAOYSA-N 2,3-dichloro-4-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=C(C#N)C(Cl)=C1Cl UVQPJOHHDFHYEE-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Hexanone Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-Nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- KOZSUGQCFHAYNB-UHFFFAOYSA-N 2-[(2,3-dichloro-6-nitrophenyl)methyl-ethylamino]acetic acid Chemical compound OC(=O)CN(CC)CC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O KOZSUGQCFHAYNB-UHFFFAOYSA-N 0.000 description 1
- XMBDUPGUTGDMHJ-UHFFFAOYSA-N 2-[(2,3-dichloro-6-nitrophenyl)methylamino]acetic acid Chemical compound OC(=O)CNCC1=C(Cl)C(Cl)=CC=C1[N+]([O-])=O XMBDUPGUTGDMHJ-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- YLFXXKJQBOJJIX-UHFFFAOYSA-N 6,7-dichloro-5,10-dihydro-3H-imidazo[2,1-b]quinazolin-2-one;hydrate;hydrochloride Chemical compound O.Cl.N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 YLFXXKJQBOJJIX-UHFFFAOYSA-N 0.000 description 1
- 229940060238 Agrylin Drugs 0.000 description 1
- 229960003555 Anagrelide hydrochloride Drugs 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N Cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229940117389 Dichlorobenzene Drugs 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N Dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N Isoamyl alcohol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 230000036650 Metabolic stability Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N Nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N Propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 210000000538 Tail Anatomy 0.000 description 1
- 230000036335 Tissue distribution Effects 0.000 description 1
- 102100015844 UBXN11 Human genes 0.000 description 1
- 101710027909 UBXN11 Proteins 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- TVWRQCIPWUCNMI-UHFFFAOYSA-N anagrelide hydrochloride Chemical compound Cl.N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 TVWRQCIPWUCNMI-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010961 commercial manufacture process Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical group [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- LMOYMHOTVOGFRM-UHFFFAOYSA-N methane;oxoplatinum Chemical compound C.[Pt]=O LMOYMHOTVOGFRM-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003510 tertiary aliphatic amines Chemical class 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 230000001732 thrombotic Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 229960002415 trichloroethylene Drugs 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N triclene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
The present invention relates to a novel process for producing anagrelide, 6,7-dichloro1,5-dihydroimidazo [2,1-b] quinazolin 2 (3H)-one, or certain analogues thereof. The process of the invention also provides improved processes for producing key intermediates required for the synthesis of anagrelide or certain analogues thereof
Description
This invention relates to a process for producing the 6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazolin 2 (3H)-one, more commonly known as anagrelide, and certain analogues thereof. More specifically, the présent invention relates to an Improved process for the formation of anagrelide and certain analogues thereof, which is efficient and viable to implement on a commercial scale.
BACKGROUND OF THE INVENTION
Anagrelide hydrochloride (Agrylin®, Xagrid®) is a novel orally administered imîdazoquinazoline which selectively reduces platelet count in humans and is used for such purposes in the treatment of myeloproliferative diseases (MPDs), such as essential thrombocythemia (ET), where an elevated platelet count may put the patient at increased thrombotic risk. The chemical structure of anagrelide, 6,7-dichloro-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one hydrochloride monohydrate, is shown as the hydrochloride monohydrate in the following formula:
HCI.H2O
WO 2008/065444 discloses certain 3- and 5-substituted anagrelide dérivatives that possess a more advantageous side effect profile. The 3- and 5-substituted anagrelide dérivatives possess dramatically lower PDE III inhibitory activity when compared to anagrelide or its active métabolite, yet they still retain potent anti-megakaryocytic activity. The compounds described in WO 2008/065444 are therefore potentially useful and bénéficiai agents for the treatment of myeloproliferative diseases, such as essential thrombocythemia.
Processes for the préparation of anagrelide are described in U.S. Patent Nos. 3,932,407; RE31.617; 4,146,718; 4,208,521; 4,357,330; and 5,801,245. Published European patent
applications EP 1373268, EP 1700840, EP 1700841, EP 1700842, EP 1700843, and EP 170859 also describe methods for preparing anagrelide.
Commercially, as discussed in US Patent No. 5,801,245, and as shown in Scheme 1 below, anagrelide has been prepared as the hydrochlorîde monohydrate (compound IV) from the intermediate, ethyl-N-(6-amino-2,3-dichlorobenzyl) glycine (compound I), either by reaction with cyanogen bromide in hot alcoholic solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent such as toluene to give the iminoquinazoline intermediate (compound II), which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base (compound III).
Scheme 1
The hydrochlorîde monohydrate anagrelide sait (compound IV) is prepared by adding hydrochloric acid to a methanol slurry of anagrelide base (compound III) and heating to reflux. The hydrochlorîde sait is then hydrated in a high humidity chamber. These two steps are time-consuming however, and the yield of hydrochlorîde sait can be poor due to competing acid hydrolysis of the lactam ring and methyl ester formation. After 15 minutes at reflux, the isolated yield is 62% and this decreases to 40% after 2 hours.
Normally, salts are prepared when the free base has undesirable properties such as poor solubility or a non-solid physical state. In this case, both anagrelide base (compound III) and the hydrochlorîde sait (compound IV) are solids with low aqueous solubility. In addition, the water of crystallization can accelerate décomposition of the parent molécule through hydrolysis of the lactam ring and this présents long-term stability problems for pharmaceutical anagrelide formulations.
Radiolabeled anagrelide base has been used in pharmacokinetic studies in humans and monkeys and results show complété absorption into blood plasma demonstrating that the base îs bioavailable. The free base is converted into the hydrochloride sait in the stomach to enhance absorption. Both the sait and the base exhibit équivalent pharmacological effects, and there is no inhérent advantage to using the hydrochloride monohydrate sait as the active pharmaceutical agent.
An important intermediate in these prior art synthèses of anagrelide is ethyl-N-(6-amino-2,3dichlorobenzyl) glycine (compound I). Ethyl-N-(6-amino-2,3-dichlorobenzyl) glycine (compound I) has been prepared from 2,3-dichloro-6-nitrobenzylamine (compound V) as shown in Scheme 2. This material is no longer readily available commercially, however, as the precursor 2,3-dichloronitrobenzonitrile has extreme toxic and skin-irritant properties.
(V)
(VI)
The conventional process for the formation of ethyl-N-(6-amino-2,3-dichlorobenzyl) glycine (compound I) from 1,2,3-trichlorobenzene is shown in U. S. Patent No. 4,146,718.
An improved process for the formation of ethyl-N-(6-amino-2,3-dichlorobenzyl) glycine (compound I) using the intermediate 2,3-dichloro-6-nitrobenzyl halide (compound Vllî), where halide is iodide, chloride or bromide, has been developed as an environmentally acceptable alternative (Scheme 3). The route of préparation from 2,3-dichloro-6-nitro-toluene (compound VII) is described in U. S. Patent No. 5,801,245, and involves a radical halogénation of the toluene group. Radical conditions can be nonselective, however, and could be difficult to effectively implement in large-scale commercial manufacture.
Scheme 3
Cl (VIII)
COOEt
In both ofthe reactions shown in Schemes 2 and 3, ethyl-N-(2,3-dichloro-6-nitrobenzyl) glycine (compound VI) is reduced to the 6-amino-2,3-dichlorobenzyl glycine (compound I) by stannous chloride réduction (SnCI2/HCI). A disadvantage of this route is the formation of large amounts of tîncontaining waste products. In addition, the strongly acidic reaction conditions can promote chlorination of the aromatic ring, producing a mixture of tri-chloro impurities which are difficult to remove in successive steps.
A further problem with these prior art process is the number of synthetic steps required to produce the quinazoline compounds, with each synthetic step leading both to a réduction in yield and increasing the possibility of competing side reactions. Thus, these conventional synthetic routes require effort to purify the intermediate and final products and may not give an optimal yield. Work up and purification may thus be needed after one or more of the intervening steps and final purification is always required.
WO 2010/070318 describes an improved process for making anagrelide and various analogues thereof. In particular, WO 2010/070318 describes a process for making 3,3-dimethylanagrelide by the process shown in Scheme 4 below.
Scheme 4
The process described in WO 2010/070318 possesses a number of advantages over the previously described processes. One particular benefit of the process described in WO 2010/070318 is that the 1,1-dimethyl-ethyl N-(2,3-dichloro-6-nitrobenzyl) glycine intermediate and its 1-unsubstituted or substituted analogues can be formed directly from the corresponding 2,3-dichloro-6-nitrobenzyl alcohol without the need to form an intermediate halo dérivative. This leads to a number of processing advantages, partîcularly on a larger scale. It will be appreciated from Scheme 4 above that WO 2010/070318 describes a three step process to get from the 2,3-dichloro-6I0 nitrobenzaldehyde intermediate to the 1,1-dimethyl-ethyl N-(2,3-dichloro-6-nitrobenzyl) glycine intermediate.
Despite the improvements offered by the process described in WO 2010/070318, there still remains a need for further improved processes for manufacturing anagrelide or analogues thereof, such as 3,3-dimethylanagrelide, which are efficient and commercially viable to implement on a commercial scale.
It is therefore an object of the présent invention to provide an improved synthetic process for the making of anagrelide and its analogues, whether in base or sait form.
It is also an aim of the présent invention to provide a synthetically efficient process for the production of anagrelide with a reduced number of synthetic steps and which avoids some or ail of the drawbacks associated with the prior art processes. It is also an aim to provide a process in which the convergency (i.e. the bringing together of synthetic fragments) is maximised. It is a further aim to ensure that the need for purification and workup is minimised. It is a particular aim of the présent invention to provide a process which minimizes the need for intermediate and final purification steps. It is thus an aim to provide a route to the compounds of formula (I) which offers an improved yield relative to the existing routes. It Is a further aim of the process of the présent invention to avoid the use of expensive and potentially hazardous reagents and to additionally minimise the complexity and costs associated with the process steps wherever possible.
It is an additional aim of the présent invention to make suitable intermediates from readily available starting materials. Ideally this is achieved by an environmentally acceptable method.
Still further objects and advantages of the présent invention will become apparent from the details provided in the spécification.
SUMMARY OF THE INVENTION
According to a first aspect of the présent invention there is provided a method for making a compound of formula (A), or a sait thereof:
wherein:
R1 and R2 are each independently hydrogen or a blocking group which functions to directly or indirectly prevent metabolic reaction at the 3- position of substitution;
V, W, X, and Y, are independently chosen from the group comprising: H, F, Cl, I, Br, CN, Ci.6 alkyl, Ci.6 haloalkyl, C^e alkoxy, C^e haloalkoxy and C^e alkanoyl; and
R7 is a Cv6 alkyl group or aryl group, each of which can be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci_6alkyl, C^ehaloalkyl, -SRfl, -OR9, -NReR9, -NO21 SCF3, halogen, -C(O)R8, -CN, and -CF3, where RB and R9 are independently H or Ct. e alkyl the process comprising the steps of:
(a) reacting a compound ofthe formula (X):
NO2
CHO with a glycine dérivative of the formula (XI)
(XI) wherein R1, R2 and R7 are as defined above;
in the presence of a suitable base and a suitable solvent to form an imine compound of the formula (X)
W.
(X) (b) reducing the imine compound of formula (XII) with a suitable reducing agent to form the compound of formula A; and (c) optionally isolating the compound of formula A in the form of an acid addition sait by reacting the compound of formula A with a suitable acid.
As indicated above, compounds of formula A are useful as intermediates in the synthesis of anagrelide and certain analogues thereof, and in particular compounds of formula (B) described below.
The process indicated above possesses a number of advantages relative to the prior art processes. In particular, with regard to the three step process defined in WO 2010/070318 for getting from the 2,3-dichloro-6-nitrobenzaldehyde intermediate to the 1,1-dimethyl-ethyl N-(2,3-dichloro-6nitrobenzyl) glycine intermediate, the process defined above requires only two key synthetic steps (steps (a) and (b) above). The process defined above has also surprisingly been found to provide an increased yield of the compound of formula A with comparable levels of purity. Furthermore, the batch cycle time can be reduced using this new process and the need to use the potentially hazardous and expensive reagent methanesulphonyl chloride, or related sulphonyl chloride dérivatives, is also eliminated, The process of the présent invention provides a further cost savîng by enabling the use of cheaper solvents, such as, for example, toluene.
In a second aspect, the présent invention provides a process for the préparation of a compound of formula (B), or a pharmaceutically acceptable sait thereof:
wherein:
R1, R2, V, W, X, and Y are ail as defined above in relation to formula A; and
R5 is H, Cm alkyl or OH;
the process comprising the steps of:
(a) forming a compound of formula A from a compound of formula (X) as defined above;
(b) reducing the compound of formula (A) to form a compound of formula (XIII):
(c) reacting the compound of formula (XIII) prepared in step (b) above with cyanogen bromide in a suitable solvent to form a compound of the formula (XIV)
J
(d) reacting the compound of formula (XIV) under cycloalkylation conditions to form the compound of formula (B); and (e) optionally thereafter forming a pharmaceutically acceptable sait of the compound of formula (B).
DETAILED DESCRIPTION OF THE INVENTION
Définitions
Unless otherwise stated, the following terms used in the spécification and claims have the following meanings:
Halo means a group selected from: fluoro, chloro, bromo or iodo.
“Alkyl” as used herein to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C16alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms. Examples of the term “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, and hexyl. A C14 alkyl group is one embodiment, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tbutyl. The same principle applies to alkyl moieties of other substiuent groups such as, for example, the alkyl moieties of an alkoxy or alkanoyl group.
“Haloalkyl refers to an alkyl group as defined above which is substituted with one or more halo atoms. Examples of the term haloalkyl include -CF3, -CHF21 -CH2CF3, -CHCI2, and -CH2CHCI2. In an embodiment, the halo atoms are selected from fluoro or chloro.
Haloalkoxy lîkewise refers to an alkoxy group that has been substituted with one or more halo atoms. Examples of the term haloalkoxy include -O-CF3 and -O-CH2CHCI2. In an embodiment, the halo atoms are selected from fluoro or chloro.
The term aryl is used herein to refer to phenyl or naphthyl, preferably phenyl.
The following are embodiments of the invention which are relevant to each of the first and second aspects of the invention.
I0 In an embodiment, Y is halo. In a particular embodiment, Y is chloro.
In an embodiment, X is halo. In a particular embodiment, X is chloro.
In an embodiment, V is H.
I5
In an embodiment, W is H.
In an embodiment, R1 is H or an optionally substituted Cj.4 alkyl or C3.8 cycloalkyl group.
In an embodiment, R2 is H or an optionally substituted Cj.4 alkyl group or C3.8 cycloalkyl.
In an embodiment, R1 and R2 are both methyl or together form a cyclopropyl group.
In a particular embodiment, R1 and R2 are both methyl.
In each of the above embodiments for R1 and R2, one or more hydrogen atoms may be replaced by deuterium. Similarly, one or more carbon atoms may be replaced by 13C.
In an embodiment, R5 is hydrogen or deuterium. In a particular embodiment, Rs is hydrogen.
In an embodiment, R7 is an optionally substituted Ci.B alkyl group, and more preferably it is methyl or ethyl.
In a particular embodiment, the compound of formula (B) is anagrelide or 3,3-dimethylanagrelîde, i.e. X and Y are chloro; V and W are hydrogen, R1 and R2 are both hydrogen or methyl; and R5 is hydrogen.
Il i
ln a particular embodiment, the compound of formula (A) is a methyl or ethyl ester of N-(2,3dichloro-6-nitrobenzyl)glycine or 1,1-dimethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine, i.e. X and Y are chloro; V and W are hydrogen, R1 and R2 are both hydrogen or methyl; and R7 is methyl or ethyl.
Préparation of compounds of Formula A
As indicated above, the présent invention provides a method for making a compound of formula (A) as defined herein, the process comprising the steps of:
(a) reacting a compound of the formula (X):
NO2
CHO with a glycine dérivative of the formula (XI)
(XI) wherein R1, R2 and R7 are as defined above;
in the presence of a suitable base and a suitable solvent to form an imine compound of the formula (XII)
(b) reducing the imine compound of formula (XII) with a suitable reducing agent to form the compound of formula A; and (c) optionally isolating the compound of formula A in the form of an acid addition sait by reacting the compound of formula A with a suitable acid.
I2 t
%
The compounds of formula X may be prepared by any suitable process known in the art. For example, methods of making a compound of formula X are described in WO 2010/070318, the entire contents of which are incorporated herein by reference.
Suitably, the compounds of formula (X) are prepared by nitrating a compound of the formula (IX) shown below:
CHO
Y (IX)
For compounds in which V and W are both hydrogen and X and Y are both chloro, the 2,3dichlorobenzaldehyde (formula IX) starting material is nitrated preferentially at the 6-position to form 2,3-dichloro-6-nitrobenzaldehyde (formula X). The 2,3-dichloro-6-nitrobenzaldehyde compound can be easily separated by crystallisation as well as by chromatography.
To enablethe nitration of the compound of formula (IX), the nitrating agent utilised is suitably nitric acid in concentrated sulphuric acid. In an embodiment, the nitrating agent is fuming nitric acid in concentrated sulfuric acid. In an alternative embodiment, lower strength nitric acid in concentrated sulphuric acid may be used, such as, for example, 60 to 80% nitric acid or, more preferably, 70% nitric acid. The use of lower strength nitric acid is less hazardous. The nitration reaction is conducted for a period of time of from 30 minutes to 5 hours. The reaction may be performed in two stages in the sense that the compound (IX) is first mixed with a solution of sulphuric acid followed by stirring for a period of from 30 minutes to 3 hours and preferably of from 1 to 2 hours. The température is maintained at a range of 10 to 50 “C and more preferably of 40 to 45 °C. The second stage of this process then involves charging the concentrated nitric acid to the solution of the compound (IX) and sulphuric acid. The resulting reaction mixture is then stirred for a period of from 30 minutes to 3 hours and preferably of from 1 to 2 hours. The température is maintained at a range of 10 to 50 qC and more preferably of 20 to 30 °C. The reaction mixture is then quenched.
In another embodiment, the compound of formula (IX) may be charged to the nitrating mixture in a single step under the same or similar conditions of température i.e. in the range of 10 to 50 °C, and stirred for a period of from 30 minutes to 5 hours before quenching.
The nitration reaction is suitably quenched by adding water to form the crude compound of formula (X) as a precipitate, Alternatively, the nitration reaction is quenched by adding the reaction mixture to water to form the compound of formula (X). The reaction is quenched at a température of between -10 and 40 °C, In some embodiments, the quenching reaction is performed towards the lower end of this range, for example 0 to 5 °C; in other embodiments, the quenching may be performed at a higher température such as 15 - 25qC. The quenching may take place immediately in the sense that water and the reaction mixture are combined immediately or may take place over an extended period such as up to 3 or 4 hours. The résultant crude compound of formula (X) can then be purified, for example by washing and recrystallisation ofthe crude product or may be used in the next step without further purification.
The glycine dérivatives of formula (XI) can be sourced commercially or synthesised using techniques well known in the art.
The reaction of step (a) between the compounds of formulae X and XI is carried out in the presence of a suitable base. The base is preferably an organic base and more preferably is an aliphatic or aromatic amine. In a particular embodiment, the base is a tertiary aliphatic amine. In a further embodiment, the base is a tri (Ονιοalkyl) amine. In a spécifie embodiment, the base is triethylamine.
The reaction between the compound of formula X and the glycine dérivative of formula (XI) is performed by dissolving the compound of formula X in a suitable solvent, such as toluene, and then adding the resulting solution to a solution of the glycine dérivative of formula (XI). Ideally the solution of the glycine dérivative is in the same solvent as the compound of formula (X). The base is then added to the resulting mixture and the reaction stirred for a period of from 1 to 4 hours, preferably with heating in order to bring the reaction to reflux.
Any suitable solvent for the step (a) reaction between the compounds of formulae X and XI may be used. Toluene, 2-methytetrahydrofuran, methanol and methyl tert-butyl ether hâve been demonstrated to work. In a particular embodiment, the solvent is toluene. Toluene is a preferred solvent because of its low cost. Other suitable solvents include: acetonitrile, chlorobenzene, chloroform, cyclohexane, dichloroethane, dichloromethane, dichlorobenzene, dimethoxyethane, DMA, DMF, dioxane, ethoxyethanol, ethyleneglycol, formamide, hexane, heptane, methoxyethanol, methylbutylketone, methylcyclohexane, N-methylpyrolidine, nitromethane, pyridine, sulfolane, tetralin, trichloroethene, xylene, anisole, butan-1-ol, butan-2-ol, butylacetate, cumene, DMSO, éthanol, diethylether, diisopropylether, ethyl acetate, isopropyl acetate, isobutylacetate, propyl acetate, methylacetate, 3-methyl-1-butanol, methylethylketone, methyl-iso-butylketone, 2-methyl-1propanol, 1-pentanol, 1-propanol, 2-propanol, tetrahydrofuran, methylisopropylketone, 1,1diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, and methylisopropylketone. One of the important aspects in the choice of the solvent for the reaction is linked to the ability to hold in solution both of the reactants.
The step (a) reaction between the compounds of formulae X and XI suitably proceeds by heating the reaction mixture to an elevated température and preferably to reflux. The reaction may proceed 10 for 1 to 24 hours, more suitably 1 to 4 hours, and most typically 2 to 4 hours.
In an embodiment, water is generated during the step (a) reaction is removed by any suitable technique known in the art. In a particutar embodiment, the water is removed azeotropically.
I5 After the reaction has been maintained at elevated température (e.g. reflux), the reaction is either allowed to cool or forcibly cooled to a température around 30 - 50 °C. Cooling may take place over a period of from 15 minutes to 2 hours. The cooled reaction mixture may then be sampled for purity. The purity of the resulting reaction mixture is such that no more than 2% w/w of the compound of formula (X) remains unreacted.
Once the step (a) reaction is complété, the product may be washed with water or an aqueous wash solution and then dried to provide the imine compound of formula (XII). Drying may be facilitated by heating the washed imine product to reflux and azeotrope drying until no more water is observed in the azeotrope collection bowl. The azeotropic drying process may be conducted for a period of from 2 to 4 hours. The dried imine is then cooled and collected. The purity of the dried product of formula XII is such that it contains no more than 1%, and preferably 0.5% w/w water.
The réduction of the imine in step (b) to yield the compound of formula A may be facilitated by any suitable reducing agent. In an embodiment, the reducing agent is a métal hydride. A particularly 30 suitable reducing agent is sodium borohydride.
In an embodiment, the réduction is facilitated by reacting sodium borohydride with acetic acid to form sodium triacetoxyborohydride as the active reducing agent species. The sodium triacetoxyborohydride species can be formed in situ or alternatively it may be preformed and added 35 to the imine of formula (XII).
I5
In an embodiment, sodium borohydride is mixed with acetic acid prior to reaction with the imine compound of formula (XII). The reaction between sodium borohydride and the acetic acid is exothermic, so the reaction vessel is suitably cooled to below 15°C. More suitably, the reaction is maintained at a température of between 0 and 10°C.
In an altemate embodiment, sodium borohydride is first added to a reaction vessel and dissolved in a solvent (e.g. toluene) before the imine of formula (XII) is added. The température of the reaction vessel may be maintained at a température of between 15 and 25°C. After addition of the imine of formula (XII), acetic acid is then added over a period of time of up to 2 hours. During the addition of the acetic acid, the reaction vessel may be maintained at a température of between 15 and 25°C.
In this embodiment the sodium triacetoxyborohydride species is generated in situ.
When the sodium triacetoxyborohydride species is preformed, the réduction reaction of step (b) is suitably conducted at a température between 10 and 40°C, more preferably between 20 and 30 °C for 1 to 24 hours, and more preferably between 6 and 12 hours (for example between 10 and 12 hours).
When the sodium triacetoxyborohydride species is generated in situ the réduction of step (b) is suitably conducted at a température of between 10 and 40°C, more preferably between 15 and 25°C for 1 to 5 hours, and more preferably between 1 and 3 hours.
Suitable solvents for step (b) are the same as for step (a) above. Suitably, the solvent for step (b) is the same as the solvent used for step (a). In an embodiment, toluene is used as the solvent in both of steps (a) and (b).
The purity of the resulting product of formula (A) is such that no more than 4%, and preferably 2%, w/w ofthe compound offormula (XII) remains unreacted.
The product of step (b) is suitably washed to remove any impurities and then the product is collected, for example by distillation. In an embodiment, the product of step (b) is washed with bicarbonate solution (e.g 15% w/w sodium bicarbonate solution) and then water and the product is collected by, for example, distillation.
Suitably, the compound of formula A is then reacted to form an acid addition sait that can be collected (as stipulated in step (c) above). Any suitable acid may be used for this purpose. In an
I
I embodiment, the acid is hydrochloric acid which yields the HCl sait ofthe compound of formula (A).
The hydrochloride sait is convenient because it facilitâtes work up and purification where needed after this reaction. In alternative embodiments, HBr or sulfonic acids, eg methanesulfonic acid, are used.
Step (c) is suitably carried out in the presence of a suitable solvent. Any suitable solvent may be used for this process. An example of a suitable solvent is an alcohol, e.g. isopropyl alcohol. As before, the choice of solvent will dépend on solubilities of the reactants; in this case the solubility of free base in the solvent is necessary to ensure the sait formation process works.
Préparation of compounds of formula B
As indicated above, the présent invention also provides a process for the préparation of a compound of formula (B), or a pharmaceutically acceptable sait thereof:
O (B) wherein:
R1, R2, V, W, X, and Y are ail as defined above in relation to formula A: and
R5 is H, Cbs alkyl or OH;
the process comprising the steps of:
(a) forming a compound of formula A from a compound of formula (X) as defined above;
(b) reducing the compound of formula (A) to form a compound of formula (XIII):
(c) reacting the compound of formula (XIII) prepared in step (b) above with cyanogen bromide in a suitable solvent to form a compound ofthe formula (XIV)
(d) reacting the compound of formula (XIV) under cycloalkylation conditions to form the compound of formula (B); and (e) optionally thereafter forming a pharmaceutically acceptable sait ofthe compound of formula (B).
In step (b) ofthe process defined above, the aromatic nitro group on the glycine dérivative of formula (A) is reduced using a conventional reducing agent One such procedure known in the art is the use of a mixture of stannous chloride and hydrochloric acid to effect the réduction. Where possible, however, the présent invention seeks to avoid the use of tin reagents. Preferred catalysts are based on metals or métal complexes of rhodium, iridium, palladium, platinum, ruthénium and osmium. In a preferred embodiment, the compounds of formula (A) are subjected to catalytic hydrogénation using a métal or metal-based catalyst such as platinum, platinum oxide, rhodium, and palladium on carbon under hydrogen pressure. The catalytic hydrogénation reaction may be carried out under homogeneous or heterogeneous conditions. Phase transfer catalysis may also be used using conventional phase transfer catalysts. A preferred catalyst is Pd/C, such as palladium on activated carbon. Once the reaction is complété, the catalyst may be removed by filtration.
In a particular embodiment, the compound of formula (A) is reacted with hydrogen in the presence of a platinum on carbon catalyst until the reaction is complété. In an embodiment, the
I8 hydrogénation step is carried out by starting at approximately atmospheric pressure of hydrogen until the rate of hydrogen uptake tails off, followed by gradually increasing the hydrogen pressure as appropriate. The hydrogen gas pressure may be from 1 to 3 bar, and is preferably 2 bar. The hydrogénation reaction is suitably carried out whilst maintaining a température of 15-25°C.
In an alternative embodiment, the hydrogénation step is carried out by pressurising the reaction vessel with hydrogen gas. Suitably the reaction proceeds for 2 to 8 hours, for example 6 hours, or until the uptake of hydrogen ceases. Suitably the pressure of the hydrogen gas in the reaction vessel is 1 to 3 bar, especially 2 bar.
Any suitable solvent may be used for the hydrogénation procedure. In an embodiment, the solvent is a water miscible solvent such as methanol. In one embodiment, the compound of formula (A) is added to a vessel containing methanol and the catalyst. Hydrogen is then întroduced into the reaction mixture as detailed above.
Suitable conditions for steps (c) and (d) in the process above are known in the art, see for example WO 2010/070318, the entire contents of which are hereby incorporated by reference. For the avoidance of doubt, the content of this disclosure insofar as it relates to steps (c) and (d) forms a part of one embodiment of the process of the présent disclosure.
In an embodiment, once the reaction in step (b) is complété and the hydrogénation catalyst has been removed, cyanogen bromide is then added and reacts with the compound of formula (XIII) to form the compound of the formula (XIV). This step (c) reaction is suitably carried out in methanol, although any other suitable water miscible solvents or solvent mixtures may also be used.
Suitably, the reaction between cyanogen bromide and the compound of formula (XIII) is facilitated by heating the reaction mixture to reflux (approximately 65 °C if the solvent is methanol). The reaction may proceed until complété. Reaction times of 2 to 12 hours, more typically 8 to 10 hours may be required. Once the reaction is complété, the reaction mixture is cooled.
The next step in the process, step (d), involves reacting the compound of formula (XIV) formed in step (c) under cycloalkylation conditions. Suitably, the cycloalkylation of the compound of formula (XIV) is facilitated by refluxing the compound in an organic alcohol in the presence of a suitable base. Any suitable base may be used. In an embodiment the base is sodium bicarbonate. In alternative embodiment, the base is sodium carbonate. The carbonate or bicarbonate may be added as an aqueous solution to the réaction mixture. Preferably, the base added to quench the
I9 reaction is sodium carbonate as this requires a much lower volume of solution to be added, which dramatically reduces the volume that needs to be filtered in order to collect the final product. This in turn reduces the filtering time dramatically, resulting in significant savings in terms of time and cost.
In an embodiment, a 15% w/w sodium carbonate solution is added and the reaction mixture is maintained at a température of 30 to 50 °C, more preferably 35 to 45 °C, for a time period of 2 to 7 hours, more preferably 3 to 5 hours. The température may then be reduced (for example to 20 to 25 °C). The cooled reaction mixture may continue to be stirred for at least one hour.
Ι0
The résultant compound of formula (B) prepared by the réaction described in step (d) may then be collected by filtration and washed (optionally with water and/or acetone) and then dried.
In step (e), the free base of the compound of formula (B) may optionally be converted into a pharmaceutically acceptable acid addition sait by dissolving the free base in a suitable solvent and adding the appropriate acid. The sait may then be collected by any suitable technique known in the art. It is not necessary for the free base of the compound of formula (B) to be isolated prior to sait formation. The desired sait can be generated by adding the appropriate acid to the crude free base prepared in step (d). The desired sait can then be collected, washed and dried in a similar manner.
The présent invention includes the synthesis of ail pharmaceutically acceptable isotopically-labelled compounds of formulae (A), (B) and (IX) to (XIV) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, (ZH and 3H), carbon, (11C, 13C and 14C), chlorine, (Î6CI), fluorine, (18F), iodine, (123l and 125l), nitrogen, (13N and 15N), oxygen, (1SO, 17O and18O), phosphorus, (32P), and sulphur, (35S).
Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, iaF, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
The skilled person will appreciate that adaptation of the methods herein described and/or adaptation of methods known in the art could be applied to the processes of the présent invention.
For example, the skilled person will be immediately familîar with standard textbooks such as Comprehensive Organic Transformations - A Guide to Functional Group Transformations, RC Larock, Wiley-VCH (1999 or later éditions), March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure, MB Smith, J. March, Wiley, (6th édition (2007) or later) Advanced Organic Chemistry, Part B, Reactions and Synthesis, FA Carey, RJ Sundberg, Kluwer
Academic/Plenum Publications, (2001 or later éditions), Organic Synthesis - The Disconnection Approach, S Warren (Wiley), (1982 or later éditions), Designing Organic Synthèses S Warren (Wiley) (1983 or later éditions), Guidebook To Organic Synthesis RK Mackie and DM Smith (Longman) (1982 or later éditions), etc., and the references therein as a guide. Procedures for conducting standard synthetic transformations may also be found at www.orgsyn.org.
A
Examples
1A. 2,3-Dichloro-6-nitrobenzaldehyde
O
1. hno3, h2so4, h2o
-----------►
2. TBME, H2O, Na2CO3
3. TBME, Heptane
Stage 1
Préparation of 2,3-DichIoro-6-nitrobenzaldehyde
Concentrated sulphuric acid (450Kg) was added to 2,3-dichlorobenzaldehyde (59Kg) and the mixture was heated to 40-44°C for 2 hours, with stirring, to dissolve ail the solids then cooled to 2025°C over a period of 95 minutes. Nitric acid (70% w/w, 34.5Kg) was added to the solution, maintaining the température between 16 and 28°C, over a period of 110 minutes. The reaction mixture was stirred for 130 minutes, at between 21-25°C, and then quenched by controlled addition over 225 minutes into 1080Kg of water (pre-cooled to 0-5°C), maintaining the température between 2-20°C, including a vessel rinse of concentrated sulphuric acid (9.2Kg). The resulting suspension was stirred for 180 minutes at between 10-14°C then isolated by filtration and washed with precooled (0-15°C) water (2 x 297Kg). The isolated crude solid (151.3Kg crude, 51.6kg active weight) was dissolved in methyl tert-butyl ether (590L) and washed with water (165L), 10% w/w sodium carbonate solution (165L) and then water (165L). Solvent was removed by reduced pressure distillation at 17-20°C until a volume of 160L was reached, whereupon heptane (1140L) was added. The resulting slurry was heated to 60°C over 54 minutes and stirred at between 60-65°C for 110 minutes, then cooled to 15-20°C over 11.5 hours. Material was isolated by filtration and washed with heptane 90L) then dried in vacuo at 40-45 °C to give 2,3-dichloro-6-nitrobenzaldehyde (21.3Kg) with 96.3% purity (HPLC) in 29% yield.
1H NMR (CDCI3, 400 MHz): 510.4 (s, 1H); 5 8.0 (d. 1 H); δ 7.8 (d, 1H)
2A. 2-aminoisobutyric acid ethyl ester hydrochloride
ο
1. SOCI2, EtOH
2. TBME
Stage 2a
O .HCl
Ethanol (395L) was added to 2-aminoisobutyric acid (79Kg) and the mixture stirred at 20°C. Thionyl chloride (91,2Kg) was added, maintaining the température at ê40°C. The mixture was heated to reflux and stirred for 6 hours. The contents were distilled under atmospheric pressure to a residual volume of approximately 200L over a period of 14 hours. The mixture was cooled to 4550°C and methyl tert-butyl ether (395L) was added. The mixture was cooled to 0-5’C and stirred for 1 hour. Material was isolated by filtration and washed with methyl tert-butyl ether (160L) precooled to 0-5°C, then dried in vacuo at 30-40°C to give ethyl 2-aminoisobutyrate hydrochloride (105.5Kg) with 86.2% purity in 71% yield (based on active).
I\l+H3 'CI
Chemical Shift (ppm) | Signal, H’s | Tentative Assignment |
1.2 | D, 3H | 1 |
1.5 | D, 6H | 7,8 |
2.5 | Quintet | DMSO |
3.4 | BS | Water |
4.2 | Quartet, 2H | 2 |
8.8 | BS, 3H* | 9 |
* = The amine has 3 protons rather than 2 because it is protonated in the HCl in the solution.
I
I
3A. Ethyl 1 -[(2,3-dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride (via the imine)
(2a) O HCl
Et3N, Toluene
Stage 2
2. IPA, HCl
Stage 2
1. NaBH4, AcOH
Part A
Ethanol (325Kg) was charged with 2-Aminoisobutyrate hydrochloride (37.1 Kg) and the mixture stirred at <20°C. Thionyl chloride (13.2Kg) was added over 10 minutes maintaining température at 15-22’C and the mixture heated to reflux (77’C) over a period of 93 minutes. The mixture was stirred at reflux for 250 minutes, cooled to £40’0, toluene (20L) was added and the mixture distilled at atmospheric pressure to a residual volume of 100L over a period of 405 minutes. Toluene (200L) was added to the residue and the mixture distilled under vacuum to a residual volume of 100L over a period of 125 minutes maintaining the température £42’C. Toluene (200L) was added to the residue and the mixture distilled under vacuum to a residual volume of 100L over a period of 180 minutes maintaining the température £44’0.
Part B
Toluene (250L) was added to 2,3-dichloro-6-nitrobenzaldehyde (46.4Kg) and the mixture stirred at 20-23 minutes until a solution forms (1 hour). The solution was added to the 2-aminoisobutyrate hydrochloride solution from part A, followed by a line rinse of toluene (SOL) Triethylamine (31.9Kg) was added to the solution over a period of 25 minutes maintaining the température between 17 and 20°C, followed by toluene (10L). The mixture was heated to 110°C and stirred under azeotropic reflux for 185 minutes at which point the in-process check indicated <2% 2,3-dichloro-6nitrobenzaldehyde remaining. The mixture was cooled to 20-25°C and washed with water (2x
225L) then heated to reflux and stirred under azeotropic reflux for 325 minutes at which point the inprocess check indicated a water content of <0.5%w/w.
Part C
Toluene (270L) was added to sodium borohydride (16Kg), the mixture stirred at 0-5°C and acetic acid (102.1 Kg) was added over a period of 190 minutes maintaining the température between 0 and 20°C, followed by toluene (1 OL). The imine solution from Part B was added to the mixture over a period of 95 minutes maintaining the température between 1-8°C, followed by toluene (50L I0 then 20L). The mixture was warmed to 20-30°C and stirred at 22-28°C for 12 hours at which point the in-process check indicated i4% imine remaining. 15% Sodium carbonate solution (370L) was added to the mixture maintaining the température between 20-30°C, the mixture stirred for 105 minutes and the layers separated. The organic layer was washed with water (225L), the organic solution concentrated in-vacuo at 18-30qC to minimum stir volume, isopropyl alcohol (675L) added 15 and the solution concentrated in-vacuo at 18-29°C to minimum stir volume. A solution of HCl in isopropyl alcohol (15.7%w/w HCl, 73.6Kg) was added to the imine solution maintaining the température between 15-21°C over a period of 22 minutes, the mixture cooled to 0-5°C over 35 minutes, stirred at 2-5°C for 135 minutes and then filtered, washed with isopropyl alcohol (2x 100L, pre-cooled to 0-5°C) and dried on the filter, until the loss on drying indicates i20%w/w, to give ethyl 20 1-((2,3-dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride (61,8Kg, active yield 57.2Kg) with
92.68% purity, by HPLC, in 75% yield.
Cl
Cl
Chemical Shift (ppm) | Signal, H’s | Tentative Assignment |
1.26 | T, 3H | 15 |
1.66 | BS, 6H | 10,11 |
4.26 | Q, 2H | 14 |
4.76 | BS, 2H | 7 |
8.07 | D, 1H | 2 |
8.24 | D, 1H | 1 |
9.88 | BS, H | 8 |
4A. 3,3-Dimethylanagreltde
Methanol (151 Kg) was added to 5% platinum on activated carbon (1.78Kg) and ethyl 1-((2,310 dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride (17.8Kg) added, followed by methanol (40Kg). The mixture was stirred under hydrogen (2bar) for 7 hours at between 20-27°C after which period the in-process check indicated reaction completion. The reaction mixture was purged under nitrogen, filtered and the filter cake washed with methanol (47.5Kg). Cyanogen bromide (7.6Kg) was added to the methanol solution of ethyl 1-[(6-amino-2,3-dichlorobenzyl)amino]isobutyrate t
» hydrochloride at 20-25°C, followed by methanol (10L) and the mixture heated to, and stirred at 6364°C for 10 hours at which point the in-process check indicated 1.7% ethyl 1-[(6-amino-2,3dichlorobenzyl)amino]isobutyrate remaining. The mixture was cooled to 38°C, 15% sodium carbonate solution (43Kg) added maintaining the température between 37-38°C and the mixture stirred at 38-40°C for 285 minutes. The mixture was cooled to 20-25°C over a period of 70 minutes, stirred at 20-25°C for 80 minutes, filtered and the filter cake slurried with water (3x 50L), then acetone (50L) and the product dried at 45°C for 8 hours to give 3,3-dimethylanagrelide (8Kg) with 99.28%w/w purity, by HPLC, in 60% yield
5A. 3,3-Dimethylanagrelide Tosylate
Part A
3,3-Dimethylanagrelide (7.1 Kg) was added to Acetone (232L), followed by a line rinse of acetone (40Kg). The slurry was stirred at 20-21 °C for 35 minutes and para-toluene sulphonic acid monohydrate (5.1 Kg), dissolved in acetone (15.4L), was added followed by a line rinse of acetone (15.4L). The mixture was heated to reflux (58°C) over a period of 52 minutes, stirred at reflux for 45 minutes, filtered, the filter washed with acetone (20L, pre-heated to 40-45°C) and the mixture concentrated by atmospheric distillation, over a period of 205 minutes, to a residual volume of approximately 90L. The solution was held at 42-49°C for 4.5 hours.
Part B
3,3-Dimethylanagrelide (7.1 Kg) was added to Acetone (232L), followed by a line rinse of acetone (40Kg). The slurry was stirred at 18-20°C for 56 minutes and para-toluene sulphonic acid monohydrate (5.1 Kg), dissolved in acetone (15.4L), added followed by a line rinse of acetone (15.4L). The mixture was heated to reflux (58°C) over a period of 25 minutes, stirred at reflux for 35 minutes, filtered, the filter washed with acetone (20L, pre-heated to 40-45°C) and the solution added to the solution formed in Part A. The mixture was heated to reflux over a period of 23 minutes and then the mixture concentrated by atmospheric distillation, over a period of 195 minutes, to a residual volume of 225L. The mixture was stirred at reflux for 20 minutes, cooled to 5°C over a period of 190 minutes and stirred at 2-5°C for 1 hour. The mixture was filtered, the filter cake washed with acetone (32L) pre-cooled to 0-5°C and the solid dried in-vacuo at 45°C for 33 hours to give 3,3-dimethylanagrelide tosylate (17.5Kg) with 99.77% purity, by HPLC, in 78% yield.
OH
Chemical Shift (ppm) | Signal, H’s | Tentative Assignment |
7.64 | D, 1H | 2 |
7.49 | D, 2H | 17, 19 |
7.13 | Q, 3H | 1, 18, 20 |
4.68 | S, 2H | 6 |
2.28 | S, 3H | 16 |
1.47 | S, 6H | 9, 10 |
B. 2,3-Dichloro-6-nitrobenzaldehyde
1. hno3, h2so4, h2o
2. TBME, H2O, Na2CO3
3. TBME, Heptane
Stage 1
Préparation of 2,3-Dichloro-6-nitrobenzaldehyde
Concentrated sulphuric acid (450Kg) was added to 2,3-dichlorobenzaldehyde (59Kg) and the mixture was heated to 40-45°0 for 1 to 2 hours, with stirring, to dissolve ail the solids then cooled to 20-25°C over a period of up to 60 minutes. Nitric acid (70% w/w, 34.5Kg) was added to the solution, maintaining the température between 15 and 30°C, over a period of up to 30 minutes. The reaction mixture was stirred for 1 to 2 hours, at between 20~30qC, and then quenched by controlled addition over a period up to 3 hours into 1080Kg of water (15-25°C), maintaining the température between 15-25°C, including a vessel rinse of concentrated sulphuric acid (9.2Kg). The resulting suspension was stirred for a period up to about 30 minutes at between 15-25’C then isolated by filtration and washed with water (15-25°C, 2 x 297Kg).
The isolated crude solid was dissolved in methyl tert-butyl ether (590L) and washed with water (165L), 10% w/w sodium carbonate solution (165L) and then water (165L). Solvent was removed by distillation at atmospheric pressure until a volume of 130L was reached. The vessel was cooled to 35-40°C whereupon heptane (1140L) was added. The resulting slurry was heated to 25-30’C. Material was isolated by filtration and washed with heptane (90L) then dried in vacuo at 40-45 °C to give 2,3-dichloro-6-nitrobenzaldehyde.
’H NMR (CDCI3l 400 MHz): Ô10.4 (s, 1H); δ 8.0 (d, 1H); Ô 7.8 (d. 1H)
2B. 2-aminoisobutyric acid ethyl ester hydrochloride
1. SOCI;,, EtOH
2. TBME
Stage 2a
Ethanol (400L) was added to 2-aminoisobutyric acid (22.0Kg). Thionyl chloride (30Kg) was added to the mixture, maintaining the température at ê40°C. The mixture was heated to reflux and stirred for a period of 4 to 6 hours. The reaction mixture was cooled to £40°C. The contents were distilled under atmospheric pressure to a residual volume of approximately 100L.
l\l+H3 'CI
Chemîcal Shift (ppm) | Signal, H’s | Tentative Assignment |
1.2 | D, 3H | 1 |
1.5 | D, 6H | 7,8 |
2.5 | Quintet | DMSO |
3.4 | BS | Water |
4.2 | Quartet, 2H | 2 |
8.8 | BS, 3H* | 9 |
* = The amine has 3 protons rather than 2 because it is protonated in the HCl in the solution.
3B. Ethyl 1 -[(2,3-dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride (via the imine)
OEt
Toluene (250L) was added to 2,3-dichloro-6-nitrobenzaldehyde (42.0Kg) and the mixture stirred until a solution forms (30 minutes). The solution was added to the 2-aminoisobutyrate hydrochloride solution from Example 2A above, followed by a line rinse of toluene (50L). Triethylamine (29Kg) was added to the solution over a period of up to about 30 minutes, followed by the addition of toluene (10L). The mixture was heated to reflux and stirred under azeotropic reflux for 3 hours at which point the in-process check indicated <2% 2,3-dichloro-6nitrobenzaldehyde remaining. The contents were washed with water (2x 225L) then heated to reflux and stirred under azeotropic reflux until no more water was observed in the azeotrope bowl. The contents were cooled to 40°C at which point the in-process check indicated a water content of <0.5%w/w.
Toluene (1 SOL) was added to sodium borohydride (7.9Kg), and the mixture stirred at 15-25°C. The imine solution obtained in the above paragraph was charged to the toluene/sodium borohydride mixture, maintaining the température at 15-25°C. A toluene line rinse was carried out (20L). Acetic acid (52Kg) was added over a period of up to 120 minutes maintaining the température between 15 and 25°C, followed by toluene (10L) as a line rinse. The mixture was stirred for no longer than 3 hours at which point the in-process check indicated £2% imine remaining.
15% Sodium carbonate solution (250L) was added to the mixture maintaining the température between 15 and 25°C, the mixture stirred for 1 to 2 hours and the layers separated. The organic layer was washed with water (225L) and the organic solution concentrated in-vacuo at no more than 60°C to minimum stir volume. A solution of HCl in isopropyl alcohol (15.7%w/w HCl) was
3!
added to the imine solution maintaining the température between 15-25°C, the mixture cooled to -5 to 0°C and stirred for 1 to 3 hours and then filtered, washed with isopropyl alcohol (2x 100L, precooled to 0-5°C) and dried on the filter, until the loss on drying indicates £5%w/w, to give ethyl 1[(2,3-dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride.
Chemical Shift (ppm) | Signal, H's | Tentative Assignment |
1.26 | T, 3H | 15 |
1.66 | BS, 6H | 10,11 |
4.26 | Q, 2H | 14 |
4.76 | BS, 2H | 7 |
8.07 | D, 1H | 2 |
8.24 | D, 1H | 1 |
9.88 | BS, H | 8 |
4B. 3,3-Dimethylanagrelide
Not isolated
1. NCBr, MeOH
2. Na2CO3(nql,· HjO, Acetone
Stage 3
Methanol (570Kg) was added to 5% platinum on activated carbon (5.3Kg) and ethyl 1 -[(2,3dichloro-6-nitrobenzyl)amino]isobutyrate hydrochloride (53.0Kg) added, followed by methanol (40Kg). Hydrogénation was then carried out by first starting at approximately atmospheric pressure until hydrogen uptake tailed off after which the hydrogen pressure was gradually increased to 2 bar 10 whilst maintaining at 15-20°C. The mixture was stirred at 15-25°C under hydrogen (2bar) until hydrogen uptake stops after which period the in-process check indicated reaction completion. The reaction mixture was purged under nitrogen, filtered and the filter cake washed with methanol (80Kg).
Cyanogen bromide (22.7Kg) was added to the methanol solution of ethyl 1-[(6-amino-2,3dichlorobenzyl)amino]isobutyrate hydrochloride at 15-25°C, followed by methanol (50L) as a line rinse and the mixture heated to, and stirred at, 63-64°C for 8 to 10 hours at which point the inprocess check indicated less than 4% ethyl 1-[(6-amino-2,3-dichlorobenzyl)amino]isobutyrate remaining. The mixture was cooled to 35-45°C, 15% sodium carbonate solution (128Kg) added maintaining the température between 35-45°C and the mixture stirred at 35-45°C for 4 - 6 hours. The mixture was cooled to 20-25°C and stirred for 60 minutes, filtered and the filter cake slurried with water (300L), then acetone (200L) and the product dried for no longer than 12 hours to give
3,3-dimethylanagrelide.
5B. 3,3-Dimethylanagrelide Tosylate
Part A
3,3-Dimethylanagrelide (20Kg) was added to acetone (800L), followed by a line rinse of acetone (16Kg) and the slurry was stirred. Para-toluene sulphonic acid monohydrate (75Kg) was mixed with acetone (178Kg) and the mixture stirred for 30 mins. The para-toluene sulphonic acid / acetone solution (50Kg) was added to the 3,3-Dimethylanagrelide / acetone solution followed by a line rinse of acetone (20L). The mixture was heated to reflux (56°C) over a period of up to 30 minutes, filtered, the filter washed with acetone (20L, pre-heated to 40-45°C) and the mixture concentrated by atmospheric distillation to a residual volume of approximately 360L. The solution was held at 35-50°C.
Part B
3,3-Dimethylanagrelide (20Kg) was added to Acetone (800L), followed by a line rinse of acetone (16Kg) and the slurry was stirred. Para-toluene sulphonic acid monohydrate (75Kg) was mixed with acetone (178Kg) and the mixture stirred for 30 mins. The para-toluene sulphonic acid / acetone solution (50Kg) was added to the 3,3-Dimethylanagrelide / acetone solution followed by a line rinse of acetone (20L). The mixture was heated to reflux (56°C) over a period of up to 30 minutes, filtered, the filter washed with acetone (20L, pre-heated to 40-45°C) and the solution added to the solution formed in Part A. The mixture concentrated by atmospheric distillation to a residual volume of approximately 360L.
The mixture was heated to reflux over a period of 15-60 minutes. The mixture was then cooled to 0-5°C ensuring a smooth cooling profile is achieved (a batch température drop of approximately 1015°C per hour). The mixture was held at 0-5°C for 30 mins. The mixture was filtered, the filter cake washed with acetone (75L) pre-cooled to 0-5°C and the solid dried to give 3,3dimethylanagrelide tosylate. The tosylate sait is a particularly convenient form of 3,3-dimethyl anagrelide because it is crystalline, soluble and easy to work with enabling further purification to high levels of purity if required.
' ’ 1
OH
Chemical Shift (ppm) | Signal, H's | Tentative Assignment |
7.64 | D, 1H | 2 |
7.49 | D, 2H | 17, 19 |
7.13 | Q, 3H | 1, 18, 20 |
4.68 | S, 2H | 6 |
2.28 | S, 3H | 16 |
1.47 | S, 6H | 9, 10 |
Claims (12)
1, A process for the préparation of a compound of formula (A), or a sait thereof:
CLAIMS wherein:
R1 and R2 are each îndependently hydrogen or a blocking group which fonctions to dlrectly or indirectly prevent metabolic réaction at the 3- position of substitution;
V, W, X, and Y, are îndependently chosen from the group comprising: H, F, Cl, I, Br, CN, Cj.g alkyl, Cj.e haloalkyl, C^e alkoxy, Cj.s haloalkoxy and Ci.6 alkanoyl; and
R7 is a Cve alkyl group or aryl group, each of which can be optionally substituted by 1 to 3 substituents îndependently selected from the group comprising: Cj.galkyl, Cj.ghaloalkyl, -SR8, -OR9, -NR8R9, -NO2, SCF3, halogen, -C(O)Re, -CN, and -CF3, where R8 and R9 are îndependently H or Cj. 6 alkyl the process comprising the steps of:
(X) with a glycine dérivative of the formula (XI) in the presence of a suitable base and a suitable solvent to form an imine compound of the formula (XII) (b) reducing the imine compound of formula (XII) with a suitable reducing agent to form the compound of formula A; and (c) optionally isolating the compound of formula A in the form of an acid addition sait by reacting the compound of formula A with an suitable acid.
2. A process for the préparation of a compound of formula (B), or a pharmaceutically acceptable sait thereof:
wherein:
t
R1, R2, V, W, X, and Y are ail as defined in claim 1; and
R5 is H, Ci-6 alkyl or OH;
the process comprising the steps of:
(a) forming a compound of formula A from a compound of formula (X) as defined above;
(b) reducing the compound of formula (A) to form a compound of formula (XIII):
(c) reacting the compound of formula (XIII) prepared in step (b) above with cyanogen bromide in a suitable solvent to form a compound of the formula (XIV) (d) reacting the compound of formula (XIV) under cycloalkylation conditions to form the compound of formula (B); and (e) optionally thereafter forming a pharmaceutically acceptable sait of the compound of formula (B).
3. A process according to claim 1 or claim 2, wherein X and Y are halo.
4. A process according to claim 3, wherein X and Y are chloro.
5. A process according to any one of the preceding claims, wherein W and V are hydrogen.
6. A process according to any one of the preceding claims, wherein R1 and R2 are both selected from hydrogen or methyl.
7. A process according to any one of the preceding claims, wherein R1 and R2 are both methyl.
8. A process according to claim 2, wherein Rs is hydrogen.
9. A process according to claim 1, wherein R7 is methyl or ethyl.
10. A process according to claim 2, wherein X and Y are chloro; V and W are hydrogen, R1 and
R2 are both methyl; and Rs is hydrogen.
11. A process according to claim 1. wherein X and Y are chloro; V and W are hydrogen, R1 and R2 are both hydrogen or methyl; and R7 is methyl or ethyl.
12. A process according to claim 1 or claim 2, wherein the compounds of formula (X) are prepared by nitrating a compound of the formula (IX) shown below:
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1017783.0 | 2010-10-21 |
Publications (1)
Publication Number | Publication Date |
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OA16582A true OA16582A (en) | 2015-11-20 |
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